Publications

The Pirbright Institute publication directory contains details of selected publications written by our researchers.

There were a total of 2071 results for your search.
Conceicao C, Thakur N, Human S, Kelly J T, Logan L, Bialy D, Bhat S, Stevenson-Leggett P, Zagrajek A K, Hollinghurst P, Varga M, Tsirigoti C, Hammond J A, Maier H J, Bickerton E, Shelton H, Dietrich I, Graham S C, Bailey D (2020)

The SARS-CoV-2 Spike protein has a broad tropism 1 for mammalian ACE2 proteins

bioRxiv, 156471

Abstract

SARS-CoV-2 emerged in late 2019, leading to the COVID-19 pandemic that continues to cause significant global mortality in human populations. Given its sequence similarity to SARS-CoV, as well as related coronaviruses circulating in bats, SARS-CoV-2 is thought to have originated in Chiroptera species in China. However, whether the virus spread directly to humans or through an intermediate host is currently unclear, as is the potential for this virus to infect companion animals, livestock and wildlife that could act as viral reservoirs. Using a combination of surrogate entry assays and live virus we demonstrate that, in addition to human ACE2, the Spike glycoprotein of SARS-CoV-2 has a broad host tropism for mammalian ACE2 receptors, despite divergence in the amino acids at the Spike receptor binding site on these proteins. Of the twenty-two different hosts we investigated, ACE2 proteins from dog, cat and rabbit were the most permissive to SARS-CoV-2, while bat and bird ACE2 proteins were the least efficiently used receptors. The absence of a significant tropism for any of the three genetically distinct bat ACE2 proteins we examined indicates that SARS-CoV-2 receptor usage likely shifted during zoonotic transmission from bats into people, possibly in an intermediate reservoir. Interestingly, while SARS-CoV-2 pseudoparticle entry was inefficient in cells bearing the ACE2 receptor from bats or birds the live virus was still able to enter these cells, albeit with markedly lower efficiency. The apparently broad tropism of SARS-CoV-2 at the point of viral entry confirms the potential risk of infection to a wide range of companion animals, livestock and wildlife.

Abstract

The chicken industry of Pakistan is a major livestock sub-sector, playing a pivotal role in economic growth and rural development. This study aimed to characterize and map the structure of broiler and layer production systems, associated value chains, and chicken disease management in Pakistan. Qualitative data were collected in 23 key informant interviews and one focus group discussion on the types of production systems, inputs, outputs, value addition, market dynamics, and disease management. Quantitative data on proportions of commodity flows were also obtained. Value chain maps were generated to illustrate stakeholder groups and their linkages, as well as flows of birds and products. Thematic analysis was conducted to explain the functionality of the processes, governance, and disease management. Major chicken production systems were: (1) Environmentally controlled production (97–98%) and (2) Open-sided house production (2–3%). Broiler management systems were classified as (I) Independent broiler production; (II) Partially integrated broiler production; and (III) Fully integrated broiler production, accounting for 65–75, 15–20, and 10–15% of commercial broiler meat supply, respectively. The management systems for layers were classified as (I) Partially integrated layer production and (II) Independent layer production, accounting for 10 and 80–85% in the egg production, respectively. The share of backyard birds for meat and eggs was 10–15%. Independent, and integrated systems for chicken production could be categorized in terms of value chain management, dominance of actors, type of finished product and target customers involved. Integrated systems predominantly targeted high-income customers and used formal infrastructure. Numerous informal chains were identified in independent and some partially integrated systems, with middlemen playing a key role in the distribution of finished birds and eggs. Structural deficiencies in terms of poor farm management, lack of regulations for ensuring good farming practices and price fixing of products were key themes identified. Both private and public stakeholders were found to have essential roles in passive disease surveillance, strategy development and provision of health consultancies. This study provides a foundation for policy-makers and stakeholders to investigate disease transmission, its impact and control and the structural deficiencies identified could inform interventions to improve performance of the poultry sector in Pakistan.

McNee A, Smith T R F, Holzer B, Clark B, Bessell E, Guibinga G, Brown H, Schultheis K, Fisher P, Ramos S, Nunez A, Bernard M, Graham S, Martini V, Chrun T, Xiao Y, Kash J C, Taubenberger J K, Elliott S, Patel A, Beverley P, Rijal P, Weiner D, Townsend A, Broderick K, Tchilian E (2020)

Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

Journal of Immunology

Abstract

mAbs are a possible adjunct to vaccination and drugs in treatment of influenza virus infection. However, questions remain whether small animal models accurately predict efficacy in humans. We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing mAbs. We show that a strongly neutralizing mAb (2-12C) against the hemagglutinin head administered prophylactically at 15 mg/kg reduced viral load and lung pathology after pandemic H1N1 influenza challenge. A lower dose of 1 mg/kg of 2-12C or a DNA plasmid-encoded version of 2-12C reduced pathology and viral load in the lungs but not viral shedding in nasal swabs. We propose that the pig influenza model will be useful for testing candidate mAbs and emerging delivery platforms prior to human trials.

Abstract

Viruses routinely employ strategies to prevent the activation of innate immune signalling in infected cells. RSV is no exception, encoding two accessory proteins (NS1 and NS2) which are well established to block Interferon signalling. However, RSV-encoded mechanisms for inhibiting NF-κB signalling are less well characterised. In this study we identified RSV-mediated antagonism of this pathway, independent of the NS1 and NS2 proteins, and indeed distinct from other known viral mechanisms of NF-κB inhibition. In both human and bovine RSV infected cells we demonstrated that the P65 subunit of NF-κB is rerouted to perinuclear puncta in the cytoplasm, puncta which are synonymous with viral inclusion bodies (IBs), the site for viral RNA replication. Captured P65 was unable to translocate to the nucleus or transactivate a NF-κB reporter following TNF-α stimulation, confirming the immune-antagonistic nature of this sequestration. Subsequently, we used correlative light electron microscopy (CLEM) to colocalise RSV N protein and P65 within bRSV IBs; granular, membraneless regions of cytoplasm with liquid organelle-like properties. Additional characterisation of bRSV IBs indicated that although they are likely formed by liquid-liquid phase separation (LLPS), they have a differential sensitivity to hypotonic shock proportional to their size. Together, these data identify a novel mechanism for viral antagonism of innate immune signalling which relies on sequestration of the NF-κB subunit p65 to a biomolecular condensate – a mechanism conserved across the Orthopneumovirus genus and not host-cell specific. More generally they provide additional evidence that RNA virus IBs are important immunomodulatory complexes within infected cells

Gizaw D, Tesfaye Y, Wood B A, Di Nardo A, Shegu D, Muluneh A, Bilata T, Belayneh R, Fentie A, Asgdome H, Sombo M, Rufael T, Tadesse F, Khan F, Yami M, Gelaye E, Wadsworth J, Knowles N J, King D P (2020)

Molecular characterisation of foot-and-mouth disease viruses circulating in Ethiopia between 2008 and 2019

Transboundary and Emerging Diseases
Publisher’s version: https://doi.org/10.1111/tbed.13675

Abstract

One of the constraints to controlling foot-and-mouth disease (FMD) in East Africa is the incomplete knowledge of the specific FMD virus (FMDV) strains circulating, and the way in which these viruses move across countries in the region. This retrospective study focuses on Ethiopia, which has one of the largest FMD-susceptible livestock populations in Africa. Analyses of FMDV positive samples collected between 2008 and 2019 demonstrate that serotypes O (n=175), A (n=51) and SAT 2 (n=33) were present in the country. Phylogenetic analysis of the VP1 sequences for these viruses showed that there were at least seven different FMD viral clades circulating during this period: O/EA-3, O/EA-4, A/AFRICA/G-I, A/AFRICA/G-IV, A/AFRICA/G-VII, SAT2/VII, and SAT2/XIII. Although these results only represent a snapshot and might not reflect all FMDV lineages that are present, they highlight the importance of serotype O, as well as the complexity and co-existence of FMDV serotypes in Ethiopia and surrounding countries. These sequence data also support the idea that there are two FMDV ecosystems existing in East Africa. Data from retrospective studies, such as these presented here, will be beneficial for vaccine selection and vaccination campaigns to control FMDV within Ethiopia.

Abstract

The positive stranded RNA genomes of picornaviruses comprise a single large open reading frame flanked by 5' and 3' untranslated regions (UTRs). Foot-and-mouth disease virus (FMDV) has an unusually large 5' UTR (1.3 kb) containing five structural domains. These include the internal ribosome entry site (IRES), which facilitates initiation of translation, and the cis-acting replication element (cre). Less well characterised structures are a 5' terminal 360 nucleotide stem-loop, a variable length poly-C-tract of approximately 100-200 nucleotides and a series of two to four tandemly repeated pseudoknots (PKs). We investigated the structures of the PKs by selective 2' hydroxyl acetylation analysed by primer extension (SHAPE) analysis and determined their contribution to genome replication by mutation and deletion experiments. SHAPE and mutation experiments confirmed the importance of the previously predicted PK structures for their function. Deletion experiments showed that although PKs are not essential for replication, they provide genomes with a competitive advantage. However, although replicons and full-length genomes lacking all PKs were replication competent, no infectious virus was rescued from genomes containing less than one PK copy. This is consistent with our earlier report describing the presence of putative packaging signals in the PK region.

van Doremalen N, Haddock E, Feldmann F, Meade-White K, Bushmaker T, Fischer R J, Okumura A, Hanley P W, Saturday G, Edwards N J, Clark M H A, Lambe T, Gilbert S C, Munster V J (2020)

A single dose of ChAdOx1 MERS provides protective immunity in rhesus macaques

Science Advances 6 (24), eaba8399

Abstract

Developing a vaccine to protect against the lethal effects of the many strains of coronavirus is critical given the current global pandemic. For Middle East respiratory syndrome coronavirus (MERS-CoV), we show that rhesus macaques seroconverted rapidly after a single intramuscular vaccination with ChAdOx1 MERS. The vaccine protected against respiratory injury and pneumonia and reduced viral load in lung tissue by several orders of magnitude. MERS-CoV replication in type I and II pneumocytes of ChAdOx1 MERS-vaccinated animals was absent. A prime-boost regimen of ChAdOx1 MERS boosted antibody titers, and viral replication was completely absent from the respiratory tract tissue of these rhesus macaques. We also found that antibodies elicited by ChAdOx1 MERS in rhesus macaques neutralized six different MERS-CoV strains. Transgenic human dipeptidyl peptidase 4 mice vaccinated with ChAdOx1 MERS were completely protected against disease and lethality for all different MERS-CoV strains. The data support further clinical development of ChAdOx1 MERS.

Abstract

Modern phylogeography aims at reconstructing the geographic diffusion of organisms based on their genomic sequences and spatial information. Phylogeographic approaches usually ignore the possibility of recombination, which decouples the evolutionary and geographic histories of different parts of the genome. Genomic regions of recombining or reassorting pathogens often originate and evolve at different times and locations, which characterised their unique spatial histories. Measuring the extent of these differences requires new methods to compare geographic information on phylogenetic trees reconstructed from different parts of the genome. Here we develop for the first time a set of measures of phylogeographic incompatibility aimed at detecting differences between geographical histories in terms of distances between phylogeographies. We study the effect of varying demography and recombination on phylogeographic incompatibilities using coalescent simulations. We further apply these measures to the evolutionary history of human and livestock pathogens, either reassorting or recombining, such as the Victoria and Yamagata lineages of influenza B and the O/Ind-2001 foot-and-mouth disease virus strain. Our results reveal diverse geographical paths of diffusion that characterise the origins and evolutionary histories of different viral genes and genomic segments. phylogeography, recombination, viral evolution.

Abstract

Mycobacterium tuberculosis (M.tb) infection results in approximately 1.3 million human deaths each year. M.tb resides primarily inside macrophages, and maintains persistent infection. In response to infection and inflammation, platelet activating factor C-16 (PAF C-16), a phospholipid compound, is released by various cells including neutophils and monocytes. We have recently shown that PAF C-16 can directly inhibit the growth of two representative non-pathogenic mycobacteria, Mycobacterium bovis BCG and Mycobacterium smegmatis (M. smegmatis), by damaging the bacterial cell membrane. Here, we have examined the effect of PAF C-16 on M. smegmatis residing within macrophages, and identified mechanisms involved in their growth inhibitory function. Our results demonstrated that exogenous PAF C-16 inhibited the growth of M. smegmatis inside phagocytic cells of monocytic cell line, THP-1; this effect was partially blocked by PAF receptor antagonists, suggesting the involvement of PAF receptor-mediated signaling pathways. Arachidonic acid, a downstream metabolite of PAF C-16 signaling pathway, directly inhibited the growth of M. smegmatis in vitro. Moreover, the inhibition of phospholipase C and phospholipase A2 activities, involved in PAF C-16 signaling pathway, increased survival of intracellular M. smegmatis. Interestingly, we also observed that inhibition of inducible nitric oxide synthase (iNOS) enzyme and antibody-mediated neutralization of TNF-α partially mitigated the intracellular growth inhibitory effect of PAF C-16. Use of a number of PAF C-16 structural analogs, including Lyso-PAF, 2-O-methyl PAF, PAF C-18 and Hexanolamino PAF, revealed that the presence of acetyl group (CH3CO) at sn-2 position of the glycerol backbone of PAF is important for the intracellular growth inhibition activity against M. smegmatis. Taken together, these results suggest that exogenous PAF C-16 treatment inhibits intracellular M. smegmatis growth, at least partially, in a nitric oxide and TNF-α dependent manner.

King S, Rajko-Nenow P, Ashby M, Frost L, Carpenter S, Batten C (2020)

Outbreak of African horse sickness in Thailand, 2020

Transboundary and Emerging Diseases
Publisher’s version: https://doi.org/10.1111/tbed.13701

Abstract

African horse sickness was confirmed in horses in Thailand during March 2020. The virus was determined to belong to serotype 1 and is phylogenetically closely related to isolates from South Africa. This is the first incidence of African horse sickness occurring in Southeast Asia and of serotype 1 outside of Africa.

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